TP9 : Patrimoine génétique et maladie, la mucoviscidose

Cette maladie est la plus fréquente des maladies héréditaires autosomiques récessives graves dans les populations d’origine européenne. Elle touche en moyenne un nouveau-né sur 2500 avec une fréquence variable selon l’origine géographique et ethnique des patients. En Europe, selon les régions, un enfant pour 1800 à 3500 naissances vivantes est atteint.

En France, un nouveau-né sur 4200 est touché par la mucoviscidose. Environ 200 enfants naissent chaque année en France avec la mucoviscidose.

Avant la découverte de traitements, cette maladie était mortelle avant l’âge de la puberté et l’on peut se demander pourquoi, dès lors que ces individus ne procréaient pas, l’allèle est encore aussi fréquent dans l’espèce humaine.

En 2008, l’espérance de vie est de 46 ans, alors qu’elle n’était que de 7 ans en 1965. Mais l’âge moyen de décès de l’ensemble des patients n’est que de 28 ans.

Problèmes :

  • En quoi la mucoviscidose est une maladie génétique?
  • Comment évaluer le risque de transmission de la mucoviscidose?
  • Comment soigner la maladie?

[important]

Consigne :
  • A l’aide des documents suivants, d’Anagène et de Rastop, montrer la relation entre les différentes échelles phénotypiques et le génotype afin de répondre aux trois problèmes.

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Document 1 : Présentation de la maladie

La mucoviscidose se caractérise  par l’obstruction par du mucus de canaux présents dans l’organisme tels que : canal pancréatique, canaux déférents, bronches et bronchioles.

Les conséquences sont de plusieurs types :

  • le pancréas ne déverse plus ses enzymes digestives dans l’intestin, la digestion est perturbée ;
  • les poumons, les bronches et les bronchioles sont encombrés par un bouchon muqueux épais difficile à évacuer, les capacités respiratoires sont fortement diminuées ;
  • les canaux déférents chez l’homme ne peuvent assurer le transport des spermatozoïdes, l’individu est stérile.

Des infections à répétition se développent dans les poumons et provoquent une dégradation du tissu pulmonaire.

L’épithélium pulmonaire est formé de cellules épithéliales et de cellules isolées ou parfois regroupées en glandes qui fabriquent le mucus tapissant les voies pulmonaires.

 Chez un sujet sain, le mucus sécrété est humide et fluide. Il piège les particules inhalées. Il est propulsé vers la gorge par les cils des cellules épithéliales où il est évacué. Chez les individus atteints de mucoviscidose, le mucus sécrété est épais, visqueux et difficile à évacuer.

Épithélium pulmonaire d’un individu sain Épithélium pulmonaire d’un individu malade

Lors d’infections bactériennes, des réactions immunitaires se mettent en place pour détruire les bactéries qui se développent dans le mucus. Ces réactions provoquent aussi la destruction du tissu pulmonaire. Les débris cellulaires des bactéries et des cellules épithéliales mortes s’accumulent alors dans le mucus, l’épaississant et le rendant encore plus difficile à évacuer.

Dans les cellules épithéliales, on a mis en évidence l’existence d’un flux d’ions Cl (chlorure) qui traverse les cellules épithéliales depuis le tissu conjonctif vers le mucus. Sans que l’on puisse expliquer le mécanisme, on constate que ce flux influence la qualité du mucus sécrété. Quand le flux a lieu, chez le sujet sain, le mucus est humide et fluide. Chez le sujet atteint de mucoviscidose, le flux n’a plus lieu, le mucus sécrété est visqueux et épais.

 La protéine responsable du flux d’ions chlorure a été découverte dans les années 1990. Cette molécule a été nommée CFTR. C’est une protéine qui fait partie de la membrane plasmique. Elle forme un canal perméable aux ions chlorure. La séquence des acides aminés de la protéine CFTR est connue.

Les protéines CFTR sont synthétisées dans le cytoplasme, puis elles migrent vers la membrane plasmique et s’y intègrent. Chez les sujets atteints de mucoviscidose, les protéines sont synthétisées. Elles sont reconnues comme « anormales » et sont détruites. Elles ne participent pas à la formation des canaux aux ions chlorure.

Document 2 : Séquence de la protéine CFTR avec Anagène et configuration spatiale avec le logiciel Rastop

[notice]- Aide pour utiliser ces deux fichiers[/notice]

Document 3 : La transmission de la mucoviscidose

Le gène impliqué dans la mucoviscidose a été identifié en 1989 : il s’agit du gène CFTR (Cytis Fibrosis Transmembrane Regulator) localisé sur le chromosome 7.

Les arbres généalogiques permettent de révéler le mode de transmission des maladies héréditaires. Dans le cas de la mucoviscidose, seuls les individus possédant deux allèles mutés sont malades. On considère qu’une personne sur 40 est porteuse d’un allèle muté responsable de la maladie (porteur sain).

[notice]- Aide pour exploiter ce document[/notice]

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